p38α‐MAPK‐deficient myeloid cells ameliorate symptoms and pathology of APP‐transgenic Alzheimer's disease mice

Abstract

Alzheimer's disease (AD), the most common cause of dementia in the elderly, is pathologically characterized by extracellular deposition of amyloid‐β peptides (Aβ) and microglia‐dominated inflammatory activation in the brain. p38α‐MAPK is activated in both neurons and microglia. How p38α‐MAPK in microglia contributes to AD pathogenesis remains unclear. In this study, we conditionally knocked out p38α‐MAPK in all myeloid cells or specifically in microglia of APP‐transgenic mice, and examined animals for AD‐associated pathologies (i.e., cognitive deficits, Aβ pathology, and neuroinflammation) and individual microglia for their inflammatory activation and Aβ internalization at different disease stages (e.g., at 4 and 9 months of age). Our experiments showed that p38α‐MAPK‐deficient myeloid cells were more effective than p38α‐MAPK‐deficient microglia in reducing cerebral Aβ and neuronal impairment in APP‐transgenic mice. Deficiency of p38α‐MAPK in myeloid cells inhibited inflammatory activation of individual microglia at 4 months but enhanced it at 9 months. Inflammatory activation promoted microglial internalization of Aβ. Interestingly, p38α‐MAPK‐deficient myeloid cells reduced IL‐17a‐expressing CD4‐positive lymphocytes in 9 but not 4‐month‐old APP‐transgenic mice. By cross‐breeding APP‐transgenic mice with Il‐17a‐knockout mice, we observed that IL‐17a deficiency potentially activated microglia and reduced Aβ deposition in the brain as shown in 9‐month‐old myeloid p38α‐MAPK‐deficient AD mice. Thus, p38α‐MAPK deficiency in all myeloid cells, but not only in microglia, prevents AD progression. IL‐17a‐expressing lymphocytes may partially mediate the pathogenic role of p38α‐MAPK in peripheral myeloid cells. Our study supports p38α‐MAPK as a therapeutic target for AD patients.

Modulation of Alzheimer’s Disease Brain Pathology in Mice by Gut Bacterial Deletion: The Role of Il-17a and Microglial MyD88

“…Indeed, the deficiency of Il-17a abolished the inflammatory inhibition induced by the deletion of gut bacteria in both microglia and brain tissue. However, knockout of Il-17a gene reduces microglial branching in APP-transgenic mice, indicating inflammatory activation of microglia, as shown in our recent project (Luo et al 2022). Thus, Il-17a regulates rather than mediates the effects of gut bacteria on the brain.…”

“…Our recent study showed that Il-17a-expressing CD4-positive lymphocytes increase in the gut and spleen of APP-transgenic mice (Luo et al 2022). We hypothesized that circulating T cells mediate the effects of intestinal bacteria on microglial activation.…”

“…Il-17a knockout (Il17a -/- ) mice were kindly provided by Y. Iwakura, Tokyo University of Science, Japan (Nakae et al 2002). Il-17a-deficient AD mice were created by cross-breeding APP/PS1-transgenic mice and Il17a -/- mice to obtain APP tg /Il17a -/- genotype in our previous study (Luo et al 2022). Microglial MyD88-haplodefficient AD mice with the APP tg MyD88 fl/wt Cre +/− genotype were generated in our previous study (Quan et al 2021) by mating APP/PS1-transgenic mice with Myd88 -floxed mice (Hou et al 2008) and Cx3Cr1-CreERT2 mice (Goldmann et al 2013) and intraperitoneal injection of tamoxifen (100 mg/kg; Sigma-Aldrich Chemie, Taufkirchen, Germany) once daily for 5 days at 1 month of age.…”

“…For the analysis of microglial morphology, our established protocol and Fiji Image J were used (Luo et al 2022). Paraffin-embedded 50-µm sagittal brain sections were used as described above.…”

“…However, transient depletion of Treg cells was shown to regulate microglia or/and infiltrated macrophages with differential effects on Aβ clearance and cognitive protection in two studies (Baruch et al 2015; Dansokho et al 2016). Our recent study showed that deficiency of p38α-MAPK in peripheral myeloid cells decreases Th17 cells, which possibly increases microglial activation and Aβ clearance in AD mice (Luo et al 2022). It is yet unknown whether Il-17a-expressing cells mediate the effects of gut bacteria on microglia.…”